Abstract 5123: The anti-tumor and anti-angiogenic effects of a lipid nanoparticle suspension of an AKT-1 anti-sense oligonucleotide
Authors: Fengyang Xie, Jia Wei, Lan Deng, Chao Wang, Ben Zhao, Robert J. Lee, Yuxin Angela Men
Journal: Cancer Research (2023)

Abstract Background: AKT-1 is known to play a critical role in cancer progression by stimulating cell proliferation and inhibiting apoptosis. AKT inhibition has been shown to inhibit tumor growth as well as tumor angiogenesis. Archexin is a fully phosphorothioated 20-mer antisense oligonucleotide, which can specifically bind to AKT-1 mRNA resulting in RNase H-based AKT-1 downregulation. WGI-0301 is a proprietary lipid nanoparticle (LNP) formulation of Archexin designed for enhanced delivery. A phase I clinical study has recently been initiated for WGI-0301 in patients with advanced solid tumors. Methods: Anti-tumor efficacy of WGI-0301 was studied in vivo in a Hepa1-6 syngeneic murine tumor model for hepatocellular carcinoma (HCC). The mice were injected i.v. with vehicle control or WGI-0301 at 8 mg/kg once weekly for 4 doses (n=8). Tumor size and body weight changes were monitored. In addition, the anti-angiogenesis activity of WGI-0301 was investigated in vitro using human umbilical vein endothelial cells (HUVEC). In the study, combination of WGI-0301 with Lenvatinib or Sorafenib were investigated to determine possible synergism. Three experimental groups were set up, including WGI-0301(0, 0.2, 2 and 20 μM), WGI-0301+ 2 μM Sorafenib, and WGI-0301+ 5 μM Lenvatinib. The cells were plated at 1.5 × 104 per well. The cells were treated with 50% Matrigel and then cultured in the 24 well plate in triplicates and were incubated for an additional 6 hours. Results: The in vivo study demonstrated anti-tumor efficacy of WGI-0301 in the Hepa1-6 model. The tumor growth inhibition % (TGI) for WGI-0301 was 46.16%, and the medium survival time (MST) of the treatment group was 55 days, which was significantly different from that of the control group (37 days). There was no severe adverse event observed during the study. In the in vitro anti-angiogenesis study, WGI-0301 alone or in combination with 2 μM Sorafenib and 5 μM Lenvatinib exhibited dose-dependent inhibition of angiogenesis. Compared with the control group, 20 μM WGI-0301 either alone or in combination with 2 μM Sorafenib and 5 μM Lenvatinib showed significantly inhibitory effect on angiogenesis. The 2 μM WGI-0301 in combination with 5 μM Lenvatinib also showed a significant inhibition effect on angiogenesis. Conclusion: Data obtained demonstrated anti-tumor and anti-angiogenesis efficacy of WGI-0301. In addition, combining WGI-0301 with Sorafenib or Lenvatinib resulted in increased anti-angiogenetic activity relative to monotherapy. WGI-0301 warrants further investigation as a selective AKT-1 inhibitor. Citation Format: Fengyang Xie, Jia Wei, Lan Deng, Chao Wang, Ben Zhao, Robert J. Lee, Yuxin Angela Men. The anti-tumor and anti-angiogenic effects of a lipid nanoparticle suspension of an AKT-1 anti-sense oligonucleotide. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5123.